The proposed project details a biologic strategy for the therapeutic targeting of nicotinic receptors of the cholinergic system for the treatment of mental and neurological disorders. The cholinergic system is an important modulatory neurotransmitter system, regulating reward, learning and memory, attention, and cognitive functions. The nicotinic acetylcholine receptor, a major receptor of the cholinergic system, is regulated by modulatory accessory proteins which bind to nicotinic acetylcholine receptors and dampen their function. Biological proof of concept studies in our mouse models indicate that regulating cholinergic tone has a beneficial enhancement of complex circuits in the brain, leading to enhanced learning and memory function. In order to develop a therapeutic intervention recapitulating this cognitive enhancement, we propose to develop a biological therapeutic to enhance cholinergic tone in the brain through accessory molecules to nicotinic receptors. Because the blood brain barrier is the most challenging problem facing the delivery of the macromolecules to neurons in the brain, we propose several strategies for optimizing delivery based on peptides with demonstrated ability to deliver therapeutic candidates past the blood- brain barrier. We will couple the most efficient translocators. We will test the functional inhibition by therapeutic candidates on our established nicotinic receptor cell lines and assays. In addition, we will label potential carrier molecules to assess their blood-brain penetrability, and finally test the efficacy of candidates in vivo in our mouse models. If successful the outcome will lead to the development of a therapeutic candidate to treat cognitive and memory impairments associated with mental and neurological disorders, such as schizophrenia, Alzheimer's and Parkinson's disease, and depression. PUBLIC HEALTH RELEVANCE: This project involves the development of therapeutic interventions to treat the cognitive dysfunction associated with mental and neurological disorders, such as schizophrenia, Alzheimer's disease, Parkinson's disease, depression, and ADHD.